{"gene":"PF3D7_1366800","run_date":"2026-09-08T16:26:55","timeline":{"discoveries":[{"year":2022,"finding":"PSS (PfPSS) localizes to the parasite endoplasmic reticulum and ER-protrusions in P. falciparum, as established by GFP-tagging and high-resolution live microscopy of transgenic parasites expressing PfPSS-GFP.","method":"GFP fusion / live fluorescence microscopy of transgenic P. falciparum parasites","journal":"Mitochondrion","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence (ER-mitochondria contact), single lab, two orthogonal imaging approaches (confocal + high-resolution microscopy)","pmids":["35623558"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"finding":"PSS (PfPSS)-containing ER-protrusions associate with the mitochondrial surface throughout the intraerythrocytic growth cycle, forming ER-mitochondria contact sites (ERMC) in P. falciparum. These contacts are stable and refractory to ER and mitochondrial stresses, indicating strong tethering complexes.","method":"High-resolution fluorescence microscopy of PfPSS-GFP transgenic parasites combined with mitochondrial co-staining and stress assays","journal":"Mitochondrion","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional consequence, single lab, multiple stress conditions tested orthogonally","pmids":["35623558"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"finding":"PSS (PfPSS) physically interacts with choline/ethanolamine-phosphotransferase (CEPT), another key enzyme in phospholipid biosynthesis, placing PSS within a protein complex at the ER that mediates phospholipid synthesis/transport.","method":"Co-immunoprecipitation / interaction assay in P. falciparum","journal":"Mitochondrion","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP reported in a single lab without reciprocal pull-down described in the abstract","pmids":["35623558"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2018,"finding":"In P. falciparum, serine incorporated into phosphatidylserine (PS) is mainly derived from the degradation of host-cell hemoglobin, establishing the metabolic input for PSS (annotated as PSS2/base-exchange enzyme) activity; the PSS-base-exchange enzyme can also catalyze Etn liberation from PS via base exchange, contributing to the ethanolamine pool for PE synthesis.","method":"Stable-isotope labeling (serine-d3, ethanolamine-d4, choline-d9) with LC/MS/MS quantification of intermediate metabolites and final phospholipids","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro metabolic flux assay with isotope tracing and MS quantification, single lab, but multiple precursors tested orthogonally","pmids":["29853527"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"In P. falciparum, PSS (PF3D7_1366800) is an ER-resident phosphatidylserine synthase that localizes to ER-protrusions which form stable ER-mitochondria contact sites (ERMC) throughout the intraerythrocytic cycle; it physically interacts with the phospholipid-biosynthetic enzyme CEPT at the ER, uses hemoglobin-derived serine as its primary substrate, and can catalyze a base-exchange reaction that also releases ethanolamine for PE synthesis."},"narrative":{"mechanistic_narrative":"PSS (PF3D7_1366800) is an endoplasmic reticulum-resident phosphatidylserine synthase of P. falciparum that couples phospholipid biosynthesis to inter-organelle membrane architecture during the intraerythrocytic cycle [PMID:35623558]. GFP-tagging and high-resolution live microscopy place PSS at the parasite ER and in ER-protrusions that associate stably with the mitochondrial surface, forming ER-mitochondria contact sites (ERMC) that persist throughout the growth cycle and resist ER and mitochondrial stress, indicating a robustly tethered contact [PMID:35623558]. Metabolically, the serine incorporated into phosphatidylserine derives mainly from degradation of host-cell hemoglobin, defining hemoglobin catabolism as the substrate input for PSS activity, and the enzyme can additionally liberate ethanolamine from PS by base exchange, feeding the ethanolamine pool for phosphatidylethanolamine synthesis [PMID:29853527]. Beyond its ER/ERMC localization, its hemoglobin-derived serine input, and a single reported interaction with the phospholipid-biosynthetic enzyme CEPT [PMID:35623558], no further mechanistic detail on PSS has been characterized in the available corpus.","teleology":[{"year":2018,"claim":"It was unclear where the serine substrate for parasite phosphatidylserine synthesis originates; isotope tracing established that PSS draws mainly on host hemoglobin-derived serine and can also run a base-exchange reaction liberating ethanolamine, linking PSS to both PS and PE metabolism.","evidence":"Stable-isotope labeling (serine-d3, ethanolamine-d4, choline-d9) with LC/MS/MS quantification in P. falciparum","pmids":["29853527"],"confidence":"Medium","gaps":["Does not identify the PF3D7_1366800 protein directly as the catalytic enzyme responsible (activity inferred from metabolic flux)","No enzymatic reconstitution or kinetic characterization of the purified protein","Relative contribution of base exchange versus other routes to the PE pool not quantified"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"claim":"The subcellular role of PSS was unknown; GFP-tagging and live imaging localized it to the ER and ER-protrusions, and showed these protrusions form stable ER-mitochondria contact sites throughout the intraerythrocytic cycle, placing PSS at a membrane-contact interface rather than diffusely in the ER.","evidence":"GFP fusion and high-resolution live fluorescence microscopy with mitochondrial co-staining and stress assays in transgenic P. falciparum","pmids":["35623558"],"confidence":"Medium","gaps":["Does not identify the molecular tether responsible for ERMC stability","Functional consequence of loss of PSS on contact-site formation or parasite viability not tested","Whether PSS catalytic activity is required for ERMC positioning is unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"claim":"Whether PSS acts alone or within a biosynthetic assembly was open; a Co-IP indicated a physical interaction with CEPT, suggesting PSS operates within an ER phospholipid-synthesis complex.","evidence":"Co-immunoprecipitation / interaction assay in P. falciparum","pmids":["35623558"],"confidence":"Low","gaps":["Single Co-IP without reciprocal pull-down described, so the interaction is not independently validated","Stoichiometry and directness of the PSS-CEPT association unknown","Functional consequence of the interaction for phospholipid flux not established"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The catalytic mechanism, structure, essentiality, and the molecular basis by which PSS-bearing ER-protrusions tether to mitochondria remain uncharacterized in the available corpus.","evidence":"","pmids":[],"confidence":"Low","gaps":["No genetic knockout/knockdown phenotype for PF3D7_1366800","No structural model or purified-enzyme kinetics","Tether identity and regulation of ERMC unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["CEPT (CHOLINE/ETHANOLAMINE-PHOSPHOTRANSFERASE) — SINGLE CO-IP, P. FALCIPARUM [#2]"],"other_free_text":["PSS-containing ER-protrusions form stable ER-mitochondria contact sites (ERMC) refractory to ER and mitochondrial stress throughout the intraerythrocytic cycle [#1].","Serine substrate for PS synthesis is mainly derived from host hemoglobin degradation [#3]."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"35623558","id":"PMC_35623558","title":"Defining ER-mitochondria contact dynamics in Plasmodium falciparum by targeting component of phospholipid synthesis pathway, phosphatidylserine synthase (PfPSS).","date":"2022","source":"Mitochondrion","url":"https://pubmed.ncbi.nlm.nih.gov/35623558","citation_count":7,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["phosphatidylserine synthase"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"32589689","id":"","title":"System-wide biochemical analysis reveals ozonide antimalarials initially act by disrupting Plasmodium falciparum haemoglobin digestion.","date":"2020","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/32589689","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PSS"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"29853527","id":"","title":"Contribution of the precursors and interplay of the pathways in the phospholipid metabolism of the malaria parasite.","date":"2018","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/29853527","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PSS"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5892,"output_tokens":1143,"usd":0.01741,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5976,"output_tokens":2145,"usd":0.041752,"stage2_stop_reason":"end_turn"},"total_usd":0.059162,"stage1_batch_id":"msgbatch_01NE1MTa8x1hW7Lo4tAaNzY1","stage2_batch_id":"msgbatch_0141vaQdeFvbo2q39AinvXM9","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"PSS (PfPSS) localizes to the parasite endoplasmic reticulum and ER-protrusions in P. falciparum, as established by GFP-tagging and high-resolution live microscopy of transgenic parasites expressing PfPSS-GFP.\",\n      \"method\": \"GFP fusion / live fluorescence microscopy of transgenic P. falciparum parasites\",\n      \"journal\": \"Mitochondrion\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence (ER-mitochondria contact), single lab, two orthogonal imaging approaches (confocal + high-resolution microscopy)\",\n      \"pmids\": [\"35623558\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PSS (PfPSS)-containing ER-protrusions associate with the mitochondrial surface throughout the intraerythrocytic growth cycle, forming ER-mitochondria contact sites (ERMC) in P. falciparum. These contacts are stable and refractory to ER and mitochondrial stresses, indicating strong tethering complexes.\",\n      \"method\": \"High-resolution fluorescence microscopy of PfPSS-GFP transgenic parasites combined with mitochondrial co-staining and stress assays\",\n      \"journal\": \"Mitochondrion\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional consequence, single lab, multiple stress conditions tested orthogonally\",\n      \"pmids\": [\"35623558\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PSS (PfPSS) physically interacts with choline/ethanolamine-phosphotransferase (CEPT), another key enzyme in phospholipid biosynthesis, placing PSS within a protein complex at the ER that mediates phospholipid synthesis/transport.\",\n      \"method\": \"Co-immunoprecipitation / interaction assay in P. falciparum\",\n      \"journal\": \"Mitochondrion\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP reported in a single lab without reciprocal pull-down described in the abstract\",\n      \"pmids\": [\"35623558\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In P. falciparum, serine incorporated into phosphatidylserine (PS) is mainly derived from the degradation of host-cell hemoglobin, establishing the metabolic input for PSS (annotated as PSS2/base-exchange enzyme) activity; the PSS-base-exchange enzyme can also catalyze Etn liberation from PS via base exchange, contributing to the ethanolamine pool for PE synthesis.\",\n      \"method\": \"Stable-isotope labeling (serine-d3, ethanolamine-d4, choline-d9) with LC/MS/MS quantification of intermediate metabolites and final phospholipids\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro metabolic flux assay with isotope tracing and MS quantification, single lab, but multiple precursors tested orthogonally\",\n      \"pmids\": [\"29853527\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"In P. falciparum, PSS (PF3D7_1366800) is an ER-resident phosphatidylserine synthase that localizes to ER-protrusions which form stable ER-mitochondria contact sites (ERMC) throughout the intraerythrocytic cycle; it physically interacts with the phospholipid-biosynthetic enzyme CEPT at the ER, uses hemoglobin-derived serine as its primary substrate, and can catalyze a base-exchange reaction that also releases ethanolamine for PE synthesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSS (PF3D7_1366800) is an endoplasmic reticulum-resident phosphatidylserine synthase of P. falciparum that couples phospholipid biosynthesis to inter-organelle membrane architecture during the intraerythrocytic cycle [#0, #1]. GFP-tagging and high-resolution live microscopy place PSS at the parasite ER and in ER-protrusions that associate stably with the mitochondrial surface, forming ER-mitochondria contact sites (ERMC) that persist throughout the growth cycle and resist ER and mitochondrial stress, indicating a robustly tethered contact [#0, #1]. Metabolically, the serine incorporated into phosphatidylserine derives mainly from degradation of host-cell hemoglobin, defining hemoglobin catabolism as the substrate input for PSS activity, and the enzyme can additionally liberate ethanolamine from PS by base exchange, feeding the ethanolamine pool for phosphatidylethanolamine synthesis [#3]. Beyond its ER/ERMC localization, its hemoglobin-derived serine input, and a single reported interaction with the phospholipid-biosynthetic enzyme CEPT [#2], no further mechanistic detail on PSS has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"It was unclear where the serine substrate for parasite phosphatidylserine synthesis originates; isotope tracing established that PSS draws mainly on host hemoglobin-derived serine and can also run a base-exchange reaction liberating ethanolamine, linking PSS to both PS and PE metabolism.\",\n      \"evidence\": \"Stable-isotope labeling (serine-d3, ethanolamine-d4, choline-d9) with LC/MS/MS quantification in P. falciparum\",\n      \"pmids\": [\"29853527\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Does not identify the PF3D7_1366800 protein directly as the catalytic enzyme responsible (activity inferred from metabolic flux)\",\n        \"No enzymatic reconstitution or kinetic characterization of the purified protein\",\n        \"Relative contribution of base exchange versus other routes to the PE pool not quantified\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The subcellular role of PSS was unknown; GFP-tagging and live imaging localized it to the ER and ER-protrusions, and showed these protrusions form stable ER-mitochondria contact sites throughout the intraerythrocytic cycle, placing PSS at a membrane-contact interface rather than diffusely in the ER.\",\n      \"evidence\": \"GFP fusion and high-resolution live fluorescence microscopy with mitochondrial co-staining and stress assays in transgenic P. falciparum\",\n      \"pmids\": [\"35623558\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Does not identify the molecular tether responsible for ERMC stability\",\n        \"Functional consequence of loss of PSS on contact-site formation or parasite viability not tested\",\n        \"Whether PSS catalytic activity is required for ERMC positioning is unresolved\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Whether PSS acts alone or within a biosynthetic assembly was open; a Co-IP indicated a physical interaction with CEPT, suggesting PSS operates within an ER phospholipid-synthesis complex.\",\n      \"evidence\": \"Co-immunoprecipitation / interaction assay in P. falciparum\",\n      \"pmids\": [\"35623558\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single Co-IP without reciprocal pull-down described, so the interaction is not independently validated\",\n        \"Stoichiometry and directness of the PSS-CEPT association unknown\",\n        \"Functional consequence of the interaction for phospholipid flux not established\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The catalytic mechanism, structure, essentiality, and the molecular basis by which PSS-bearing ER-protrusions tether to mitochondria remain uncharacterized in the available corpus.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No genetic knockout/knockdown phenotype for PF3D7_1366800\",\n        \"No structural model or purified-enzyme kinetics\",\n        \"Tether identity and regulation of ERMC unknown\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003882\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0008444\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0044233\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006659\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0006646\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CEPT (choline/ethanolamine-phosphotransferase) — single Co-IP, P. falciparum [#2]\"\n    ],\n    \"other_free_text\": [\n      \"PSS-containing ER-protrusions form stable ER-mitochondria contact sites (ERMC) refractory to ER and mitochondrial stress throughout the intraerythrocytic cycle [#1].\",\n      \"Serine substrate for PS synthesis is mainly derived from host hemoglobin degradation [#3].\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1366800","name":null,"product":"phosphatidylserine synthase","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1142700","name":null,"product":"phosphatidylserine synthase, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1104500","name":null,"product":"phosphatidylserine synthase, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"PSS","evaluation":null}